The present invention relates to new non-phosphorylatable, non-nucleoside pyrrolo[2,3-d]pyrimidines and their use in the treatment of viral infections.
Broad spectrum antiviral activity of pyrrolo[2,3-d]pyrimidine nucleosides such as tubercidin, sangivamycin and toyocamycin and some substituted derivatives previously has been reported. Activity of those compounds against specific viruses, such as RNA rhinovirus and DNA herpes simplex virus type 1 and type 2 also has been reported. See, for example, Bergstrom, D. E. et al., J. Med. Chem. 27:285-292 (1984); and DeClercq, E. et al., Antimicrob. Agents Chemother., 29:482-487 (1986).
Pyrrolo[2,3-d]pyrimidine nucleosides are particularly attractive as potential antiviral agents because of their stability toward the action of two major enzymes of bioactive purine nucleoside inactivation, deamination by adenosine deaminase and glycosidic bond cleavage by purine nucleoside phosphorylases. Unfortunately, many of the pyrrolo[2,3-d]pyrimidine nucleosides which have been previously described as having potential antiviral activity also exhibit unacceptable levels of cytotoxicity, thereby diminishing their usefulness in treatment of viral infections.
A number of pyrrolo[2,3-d]pyrimidine nucleoside derivatives which exhibit improved antiviral activity and more acceptable levels of cytotoxicity than tubercidin, sangivamycin, toyocamycin and thiosangivamycin have been reported. These prior art pyrrolo[2,3-d]pyrimidine nucleoside derivatives are described below.
Townsend et al. (U.S. Pat. No. 4,892,865) disclose the use of, inter alia, several 4-amino-pyrrolo[2,3-d]pyrimidine-5-carbonitriles and 4-aminopyrrolo[2,3-d]pyrimidine-5-thiocarboxamides substituted at the 7-position with 2xe2x80x2,3xe2x80x2-dideoxy-2xe2x80x2,3xe2x80x2-didehydro-xcex2-D-ribofuranose and 2xe2x80x2,3xe2x80x2-dideoxyribofuranose as antiviral agents.
Renau et al. (Bioorg. and Med. Chem. Lett., 2:1755-1760, 1992) disclose the use of, inter alia, 4-amino-pyrrolo[2,3-d]pyrimidine -5-thiocarboxamides and 4-amino-pyrrolo[2,3-d]pyrimidine-5-carbonitriles substituted at the 7-position with xcex2-D-ribofuranose as antiviral agents.
A number of pyrrolo[2,3-d]pyrimidine non-nucleoside derivatives which exhibit improved antiviral activity and more acceptable levels of cytotoxicity than tubercidin, sangivamycin, toyocamycin and thiosangivamycin as well as the nucleoside derivatives described above have been reported. These prior art pyrrolo[2,3-d]pyrimidine non-nucleoside derivatives are described below.
Townsend et al. (U.S. Pat. Nos. 4,927,830 and 4,968,686) disclose the use of, inter alia, several 4-amino-pyrrolo[2,3-d]pyrimidine-5-thiocarboxamides and 4,6-diamino-pyrrolo[2,3-d]pyrimidine-5-thiocarboxamides variously substituted at the 7-position with xe2x80x94CH2OCH(CH2OH)2, xe2x80x94CH2OCH2CH2OH and xe2x80x94CH(CH2OH)(OCH(CH2OH)2) as antiviral agents.
Gupta et al. (J. Med. Chem., 32: 402-408, 1989) disclose the use of, inter alia, several 4-amino-pyrrolo[2,3-d]pyrimidine-5-thiocarboxamides and 4-amino-pyrrolo[2,3-d]pyrimidine-5-carbonitriles variously substituted at the 7-position by xe2x80x94CH2OCH(CH2OH)2 and xe2x80x94CH(CH2OH)(OCH(CH2OH)2) as antiviral agents.
Gupta et al. (J. Med. Chem., 32:1420-1425, 1989) disclose the use of, inter alia, several 4-amino.-pyrrolo[2,3-d]pyrimidine-5-thiocarboxamides and 4-amino-pyrrolo[2,3-d]pyrimidine-5-carbonitriles substituted at the 7-position by xe2x80x94CH2OCH2CH2OH as antiviral agents.
Renau et al. (Antiviral Res., 19:15-28, 1992) disclose the use of 4-amino-pyrrolo[2,3-d]pyrimidine-5-thiocarboxamide and 4-aminopyrrolo[2,3-d]pyrimidine-5-carbonitrile substituted at the 7-position by xe2x80x94CH2xe2x80x94OCH2xe2x80x94CH2xe2x80x94OH as antiviral agents.
Swayze et al. (Nucleosides and Nucleosides, 11:1507-1527, 1992) disclose the use of, inter alia, 4,6-diamino-pyrrolo[2,3-d]pyrimidine -5-thiocarboxamides and 4,6-diamino-pyrrolo[2,3-d]pyrimidine-5carbonitriles variously substituted at the 7-position by xe2x80x94CH2xe2x80x94OCH2xe2x80x94CH2xe2x80x94OH and xe2x80x94CH2 xe2x80x94OCH(CH2xe2x80x94OH)2 as antiviral agents.
A limited number of pyrrolo[2,3-d]pyrimidine non-nucleoside, non-phosphorylatable derivatives which exhibit improved antiviral activity and more acceptable levels of cytotoxicity than tubercidin, sangivamycin, toyocamycin and thiosangivamycin as well as the nucleoside derivatives described above have been reported.
For example, Renau et al. (Bioorg and Med Chem. Lett., 2:1755-1760, 1992) disclose the use of, inter alia, several 4-amino-pyrrolo[2,3-d]pyrimidine-5-thiocarboxamides and 4-amino-pyrrolo[2,3-d]pyrimidine-5-carbonitriles variously substituted at the 7-position with xe2x80x94CH2xe2x80x94OCH2xe2x80x94CH2xe2x80x94OH, xe2x80x94CH2xe2x80x94OCH(CH2xe2x80x94OH)2, CH3, xe2x80x94CH2xe2x80x94CHxe2x95x90CH2, and xe2x80x94CH2xe2x80x94CH2xe2x80x94CH3 as antiviral agents.